Pelizaeus-Merzbacher Disease with PLP1 Exon 1 Duplication, Previously Misdiagnosed as Cerebral Palsy: a Case Report

Pelizaeus-Merzbacher disease (PMD) is a X-linked recessive disorder with dysmyelination in central nervous system caused by proteolipid protein 1 (PLP1) gene mutation. We report a case of PMD with PLP1 exon 1 duplication, previously misdiagnosed as cerebral palsy (CP). A 25-year-old male previously diagnosed as CP visited our clinic with progressive weakness and spasticity of bilateral lower limbs. Next generation sequencing revealed hemizygous duplication of exon 1 in PLP1. Additionally, multiplex ligation-dependent probe amplification assay of the patient's mother showed the same mutation, which could finally confirm the diagnosis as PMD. This patient received comprehensive rehabilitation program, and helped the patient to achieve functional improvement. Proper diagnosis and therapeutic plan will be needed for the patients with PMD, before diagnosing CP rashly.ope

Chromosomal Deletion in 7q31.2-31.32 Involving Ca2+-Dependent Activator Protein for Secretion Gene in a Patient with Cerebellar Ataxia: a Case Report

We present a 33-year-old male patient with cerebellar ataxia. He was first considered to have a psychiatric conversion disorder but finally found to have chromosomal deletion in 7q31.2-31.32 involving Ca2+-dependent activator protein for secretion (CADPS) gene. When a targeted gene sequencing using next-generation sequencing panel and chromosomal microarray analysis were performed, an 8.6 Mb deletion within chromosome 7q31.2-31.32 was discovered. Deletion of CADPS gene in the 7q31.2-31.32 was suggested as the causative factor of cerebellar ataxia. Functional levels evaluated by Berg balance scale and modified Barthel index were improved via comprehensive rehabilitation including balance training and a dopamine agonist medication. To the best of our knowledge, this is the first report of chromosomal deletion in 7q31.2-31.32 including CADPS gene detected in patients with cerebellar ataxia.ope

Juvenile Parkinsonism with PARK2 Gene Mutation Misdiagnosed as Dopa-responsive Dystonia: a Case Report

Parkinson's disease is prevalent in elderly patients, usually aged over 50 years. If clinical symptoms of parkinsonism appear before 21 years of age, it is called juvenile parkinsonism (JP). JP may present atypical features such as dystonia, and is often misdiagnosed as other diseases, including dopa-responsive dystonia (DRD). Here, we report a case of JP with PARK2 mutation misdiagnosed as DRD. A 32-year old female, who presented dystonia of both legs, was initially diagnosed with hereditary spastic paraplegia and showed a dramatic response to low-dose L-dopa, which led to the diagnosis of DRD. However, Parkinson's disease caused by a mutation in the PARK2 gene was later diagnosed via next-generation sequencing. Accurate understanding of JP is necessary for early diagnosis and comprehensive management of movement disorders at a young age.ope

Parasympathetic Effect Induces Cell Cycle Activation in Upper Limbs of Paraplegic Patients with Spinal Cord Injury

The present study aimed to investigate gene expression changes related to cell cycle activation in patients with spinal cord injury (SCI) and to further evaluate the difference between the upper and lower limbs of SCI patients. Fibroblasts were obtained from the upper and lower limbs of SCI patients and healthy subjects. To investigate gene expression profiling in the fibroblasts from SCI patients compared to the healthy subjects, RNA-Seq transcriptome analysis was performed. To validate the parasympathetic effects on cell cycle activation, fibroblasts from upper or lower limbs of SCI patients were treated with the anticholinergic agents tiotropium or acetylcholine, and quantitative RT-PCR and Western blot were conducted. Cell proliferation was significantly increased in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. The pathway and genes involved in cell cycle were identified by RNA-Seq transcriptome analysis. Expression of cell-cycle-related genes CCNB1, CCNB2, PLK1, BUB1, and CDC20 were significantly higher in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. When the fibroblasts were treated with tiotropium the upper limbs and acetylcholine in the lower limbs, the expression of cell-cycle-related genes and cell proliferation were significantly modulated. This study provided the insight that cell proliferation and cell cycle activation were observed to be significantly increased in the upper limbs of SCI patients via the parasympathetic effect.ope

Reduced Interaction of Aggregated α-Synuclein and VAMP2 by Environmental Enrichment Alleviates Hyperactivity and Anxiety in a Model of Parkinson's Disease

Parkinson's disease (PD) is a prevalent motor disease caused by the accumulation of mutated α-synuclein (α-Syn); however, its early stages are also characterized by non-motor symptoms, such as olfactory loss, cognitive decline, depression, and anxiety. The therapeutic effects of environmental enrichment (EE) on motor recovery have been reported, but its effects on non-motor symptoms remain unclear. Herein, we reveal the beneficial effects of EE on PD-related non-motor symptoms and changes in synaptic plasticity in the nucleus accumbens. To investigate its therapeutic effects in the early phase of PD, we randomly assigned eight-month-old mice overexpressing human A53T (hA53T) α-Syn to either the EE or standard condition groups for two months. Next, we performed behavioral tests and biochemical and histological analyses at 10 months of age. EE significantly alleviated locomotor hyperactivity and anxiety during the early stages of PD. It normalized the levels of tyrosine hydroxylase, phosphorylated and oligomeric α-Syn, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex-forming proteins, including synaptosomal-associated protein, 25 kDa, syntaxin1, and vesicle-associated membrane protein 2 (VAMP2). Moreover, the interactions between VAMP2 and pSer129 α-Syn were markedly reduced following EE. The restoration of synaptic vesicle transportation status may underlie the neuroprotective effects of EE in hA53T α-Syn mice.ope

Evaluation of Sexual Function in Adults with Cerebral Palsy

Objective: To investigate current status of psychosexual function in adults with cerebral palsy (CP) by Derogatis Sexual Functioning Inventory (DSFI), which is a widely used multidimensional measure of sexual functioning. Method: Forty-two adults with CP and 150 healthy controls participated in this study. All participants were interviewed with DSFI, which consisted of 10 domains such as sexual information, experience, drive, attitude, psychological symptoms, affect, gender role, fantasy, body image and satisfaction. Results: Adults with CP showed significantly lower scores in sexual information, experience and satisfaction, and higher scores in psychological distress symptoms and conservative attitude, compared with controls (p＜0.05). Especially, unmarried men with CP had a significant sexual dysfunction in most substantive domains of DSFI (p＜0.05). However, there was no statistical difference in married men, unmarried women and married women, compared with normal controls. Sexual experience, drive, body image and satisfaction were significantly distressed in non-ambulatory CP, compared with functional ambulators (p＜0.05). The score of sexual satisfaction had a significant relationship with those of sexual experience, attitude, psychological symptoms and body image in adults with CP (p＜0.05). Conclusion: Adults with CP showed a distress in psychosexual functioning, especially in unmarried men and non- ambulators. Therefore, active interventions of sexual counseling and education will be helpful for enhancing their sexual function.ope

High-Frequency Repetitive Magnetic Stimulation Enhances the Expression of Brain-Derived Neurotrophic Factor Through Activation of Ca(2+)-Calmodulin-Dependent Protein Kinase II-cAMP-Response Element-Binding Protein Pathway

Repetitive transcranial magnetic stimulation (rTMS) can be used in various neurological disorders. However, neurobiological mechanism of rTMS is not well known. Therefore, in this study, we examined the global gene expression patterns depending on different frequencies of repetitive magnetic stimulation (rMS) in both undifferentiated and differentiated Neuro-2a cells to generate a comprehensive view of the biological mechanisms. The Neuro-2a cells were randomly divided into three groups-the sham (no active stimulation) group, the low-frequency (0.5 Hz stimulation) group, and high-frequency (10 Hz stimulation) group-and were stimulated 10 min for 3 days. The low- and high-frequency groups of rMS on Neuro-2a cells were characterized by transcriptome array. Differentially expressed genes were analyzed using the Database of Annotation Visualization and Integrated Discovery program, which yielded a Kyoto Encyclopedia of Genes and Genomes pathway. Amphetamine addiction pathway, circadian entrainment pathway, long-term potentiation (LTP) pathway, neurotrophin signaling pathway, prolactin signaling pathway, and cholinergic synapse pathway were significantly enriched in high-frequency group compared with low-frequency group. Among these pathways, LTP pathway is relevant to rMS, thus the genes that were involved in LTP pathway were validated by quantitative real-time polymerase chain reaction and western blotting. The expression of glutamate ionotropic receptor N-methyl d-aspartate 1, calmodulin-dependent protein kinase II (CaMKII) delta, and CaMKIIalpha was increased, and the expression of CaMKIIgamma was decreased in high-frequency group. These genes can activate the calcium (Ca(2+))-CaMKII-cAMP-response element-binding protein (CREB) pathway. Furthermore, high-frequency rMS induced phosphorylation of CREB, brain-derived neurotrophic factor (BDNF) transcription via activation of Ca(2+)-CaMKII-CREB pathway. In conclusion, high-frequency rMS enhances the expression of BDNF by activating Ca(2+)-CaMKII-CREB pathway in the Neuro-2a cells. These findings may help clarify further therapeutic mechanisms of rTMS.ope

Cell Surface Antigen Display for Neuronal Differentiation-Specific Tracking

Cell therapeutic agents for treating degenerative brain diseases using neural stem cells are actively being developed. However, few systems have been developed to monitor in real time whether the transplanted neural stem cells are actually differentiated into neurons. Therefore, it is necessary to develop a technology capable of specifically monitoring neuronal differentiation in vivo. In this study, we established a system that expresses cell membrane-targeting red fluorescent protein under control of the Synapsin promoter in order to specifically monitor differentiation from neural stem cells into neurons. In order to overcome the weak expression level of the tissue-specific promoter system, the partial 5' UTR sequence of Creb was added for efficient expression of the cell surface-specific antigen. This system was able to track functional neuronal differentiation of neural stem cells transplanted in vivo, which will help improve stem cell therapies.ope

Word Lexicality- and Regularity-Dependent Alexia in Alzheimer’s Disease

Objectives : Despite a great deal of observation on subsequent alexia for Hangeul due to Alzheimer's disease (AD), there is a paucity of research on alexia in Korean AD patients. The purpose of this study is to identify characteristics of alexia of AD according to word lexicality and regularity. Methods : AD patients under GDS 3–6 on the Global Deterioration Scale and NE (normal elderly) groups of 20, were to read aloud three word types (regular words, irregular words, nonwords). Results : The findings revealed that the AD group had significantly higher error frequency when reading regular and irregular words and nonwords compared with the NE group. In addition, there were lexicality and regularity effects in the AD group. From the error analyses of the AD group reading irregular words, visual error was the most frequent, followed by regularization and misapplication of phonological rules. Conclusion : Unsurprisingly, AD patients using Hangeul manifested diverse word classification errors. This research is noteworthy in that it is the first study on the AD subject group reading Hangeul.ope

Sympathetic Vasomotor Response with Stress Digital Infrared Thermal Imaging in Normal Healthy Subjects

Objective: To investigate sympathetic vasomotor response of the hands to cold and warm stress on the foot with Digital Infrared Thermal Imaging (DITI) in normal healthy subjects. Method: Fifteen healthy subjects were participated in this study. The DITI was taken during immersing right foot in cold and warm water bath. The thermal images of the dorsal hands were captured at the starting point and then every 5-minute up to 30 minutes. The ratio of temperature between the ending point (30T) and the starting point (0T) was calculated. Results: In cold stress test, the mean 30T/0T ratio were 92.8⁑2.4% and 92.2⁑2.7% in the right and left hands, respectively. There were no statistically significant side to side differences. The temperature of the each hand was significantly lowered at every 5 minutes interval (p＜0.05). In warm stress test, the mean 30T/0T ratio were 104.5⁑1.8% and 104.4⁑2.0% in the right and left hands, respectively. The temperature of each hand was significantly increased at the first 5 minutes (p＜0.05), and tended to increase until 10 minutes. After then, the temperature was not significantly changed until 30 miniutes. Conclusion: We could identify the normal sympathetic vasomotor response to the cold and warm stress with DITI. It might be served as an useful baseline data for the identification of sympathetic dysfunction.ope